Higado Graso

Machine Translated by Google
seminar
Non-alcoholic fatty liver disease

Elizabeth E Powell, Vincent Wai-Sun Wong, Mary Rinella
Lancet 2021; 397:2212–24 Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is a leading cause of cirrhosis
published online and hepatocellular carcinoma. NAFLD encompasses a disease continuum from steatosis with or without
April 21, 2021 mild inflammation (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH), which is characterized
https://doi.org/10.1016/
by necroinflammation and faster fibrosis progression than non-alcoholic fatty liver. NAFLD has a bidirectional
S0140-6736(20)32511-3
Center for Liver Disease
association with components of the metabolic syndrome, and type 2 diabetes increases the risk of cirrhosis
Research, Faculty of Medicine,
and related complications. Although the leading causes of death in people with NAFLD are cardiovascular
University of Queensland, disease and extrahepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related
Translational Research
outcomes and overall mortality, and can be assessed with combinations of non-invasive tests. Patients with
Institute, Brisbane, QLD.
cirrhosis should be screened for hepatocellular carcinoma and oesophageal varices. There is currently no
Australia (Prof EE Powell MD);
Department of
approved therapy for NAFLD, although several drugs are in advanced stages of development. Because of
Gastroenterology and the complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is likely to
Hepatology, Princess Alexandra Healthy lifestyle and weight reduction remain crucial to the prevention and treatment of NAFLD.
Hospital, Brisbane, QLD,
Australia (Prof EE Powell);
Introduction highlight progress in non-invasive tests to assess liver
Department of Medicine and
Therapeutics, Chinese Over the past four decades, non-alcoholic fatty liver disease severity and the importance of a collaborative
University of Hong Kong, disease (NAFLD) has become the most common chronic approach to diagnosis, risk stratification, and management
Hong Kong Special
liver disorder (with a global prevalence of around 25% of to improve health outcomes for people with NAFLD.
Administrative Region, China
(Prof V WS Wong MD); State the adult population)1 and is recognized to have a close,
Key Laboratory of Digestive bidirectional association with components of metabolic Definition
Disease, Chinese University of syndrome.2 Although less than 10% of people with NAFLD is the liver component of a cluster of conditions
Hong Kong, Hong Kong Special
NAFLD develop liver-related complications, a key that are associated with metabolic dysfunction. Although
Administrative Region, China
(Prof V WS Wong); challenge is to identify those who are at the highest risk fatty liver hepatitis resulting in cirrhosis was described
Northwestern University, among the many people affected by NAFLD. Due to its nearly 20 years beforehand,8 the term non-alcoholic
Feinberg School of Medicine, high prevalence, NAFLD is now the most rapidly steatohepatitis (NASH) was first coined by Ludwig and
Chicago, IL, USA
(Prof M Rinella MD)
increasing cause of liver-related mortality worldwide3 colleagues in 1980.9 NAFLD is defined by the presence
and is emerging as an important cause of end-stage liver of steatosis in more than 5% of hepatocytes in association
Correspondence to:
Prof Elizabeth E Powell, disease,4 primary liver cancer,5 and liver transplantation with metabolic risk factors (particularly, obesity and type
Department of Gastroenterology with a substantial health economic burden. Despite the 2 diabetes) and in the absence of excessive alcohol
and Hepatology, Princess growing concern, NAFLD is underappreciated as an consumption (ÿ30 g per day for men and ÿ20 g per day
Alexandra Hospital, Brisbane,
important chronic disease6 and there are few national for women) or other chronic liver diseases.10 Current
QLD 4102, Australia
[email protected] strategies or policies for NAFLD.7 nomenclature suggests that NAFLD is more of a
This Seminar describes the epidemiology, natural diagnosis of exclusion than of inclusion, and there is an
history, and risk factors for progression of NAFLD. We ongoing debate about the limitations of the present
terminology and diagnostic criteria.11,12 In 2020, an
international panel of experts proposed the concept of
Search strategy and selection criteria metabolic dysfunction-associated fatty liver disease
We searched PubMed and MEDLINE to identify studies and (MAFLD) to highlight the contribution of cardiometabolic
reviews published between Jan 1, 1980, and Dec 31, 2020, risk factors to the development and progression of liver
relevant to the scope of this Seminar with the terms disease (even among patients with other liver diseases);11
“non-alcoholic fatty liver disease”, “non-alcoholic however, MAFLD is not the currently accepted
steatohepatitis”, “ NAFLD”, “NASH”, “fatty liver”, nomenclature by the American Association for the Study
“epidemiology”, “prevalence”, “incidence”, “disease burden”, “non- of Liver Diseases or the European Association for the Study of Live
invasive tests”, “liver fibrosis”, “blood tests”, “liver stiffness NAFLD is an umbrella term for a broad range of
measurement ”, “natural history”, “pathogenesis”, “treatment”, clinical nicopathological findings. Histologically, NAFLD
“pharmacotherapy”, and “risk stratification”. encom passes a disease continuum (figure 1 A–C) that
Articles were considered regardless of language. We selected includes steatosis with or without mild inflammation (non-
references that provided current, evidence-based insight into nonalcoholic fatty liver, NAFL) and a necroinflammatory
alcoholic fatty liver disease. Most of the selected articles subtype (NASH), which is additionally characterized by
were published within the past 5 years, although we also included the presence of hepatocellular injury (hepatocyte ballooning).
highly referenced, older publications that contributed to new The predominant drivers of disease can vary substantially
knowledge or understanding of non-alcoholic fatty liver among patients with NAFLD. Furthermore, disease
disease. progression and response to treatment are heterogeneous.
Information about disease activity and, in particular, the
2212 www.thelancet.com Vol 397 June 5, 2021

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TO B. C.
D. AND F
Figure 1: Histological and radiological assessment of non-alcoholic fatty liver disease

(A) Non-alcoholic fatty liver is characterized by macrovesicular steatosis (large round non-staining areas represent lipid droplets in hepatocytes [gray arrow];
haematoxylin and eosin stain; magnification×40) with no or little necroinflammation. (B) Apart from fat accumulation, non-alcoholic steatohepatitis (NASH) is
characterized by the presence of lobular inflammation and hepatocyte ballooning. At the center of the image is a ballooned hepatocyte surrounded by inflammatory
cells (red arrow; haematoxylin and eosin stain; magnification×40). (C) As disease progresses, accumulating liver fibrosis will eventually result in cirrhosis. On the
right of this image is a cirrhotic nodule surrounded by thick fibrous tissue. In some cases, steatosis and necroinflammation might reduce or disappear as the
disease progresses to cirrhosis, a condition referred to as burned-out NASH (sirius red; magnification×10). (D) Ultrasonography, the most common method to
diagnose fatty liver, characterized by bright liver echotexture (yellow bracket) and blurring of deeper structures (red arrow). (E) Vibration-controlled transient
elastography, a point-of-care measurement of liver stiffness for the estimation of fibrosis that can also estimate hepatic steatosis using the controlled attenuation
parameter. The machine is equipped with an M-mode ultrasound for the localization of liver parenchyma (green triangle). The elastogram (red arrow) represents
the measurement of liver stiffness. A steeper slope indicates that the shear-wave velocity is higher, and the liver is stiffer. (F) Magnetic resonance elastography of a
patient with NASH cirrhosis, currently one of the most accurate non-invasive tests of liver fibrosis, with the color scheme reflecting stiffness in different parts of the
liver. Red color shows areas with greater stiffness (yellow circle).
Extent of liver fibrosis is necessary to assess the severity disease prevalence. In people with other conditions (eg,
of liver disease and provide prognostic information. alcohol-related liver disease, and viral or autoimmune
Growing insights from metabolomics, genomics, and hepatitis), fatty liver frequently coexists and might have a
other areas will enable disease phenotyping and facilitate synergistic role in liver injury.19 Importantly, the disease
potential disease stratification in the future. and economic burden of NAFLD will probably increase
during the coming decades.20,21 Health-care utilization
Epidemiology and disease burden and expenditure are particularly high among patients with
NAFLD is now the most common cause of chronic liver NAFLD and advanced fibrosis or type 2 diabetes and
disease worldwide, with a prevalence that varies from 13 those requiring hospital admission.22,23
5% in Africa to 31 8% in the Middle East,1 which is likely Little information is available regarding the effect of
driven by differences in overall caloric intake , physical NAFLD on patients' daily lives,24 which will be important
activity, body fat distribution, socioeconomic status, and data to collect in future intervention or treatment studies.
genetic composition. Because of its close association
with the metabolic syndrome, NAFLD is seen in 47 3–63 The number of cases of childhood obesity, an important
7% of people with type 2 diabetes and up to 80% of risk factor for NAFLD, is still increasing; in the USA, the
people with obesity.13,14 However, some people with a prevalence of obesity among children aged 2–5 years
healthy body- mass index (eg, <25 kg/m² in White people increased from 8 4% in 2011–12 to 13 9% in 2015–16.25
and <23 kg/m² in Asian people) can still develop NAFLD, Although the increase appears to have slowed in many
often described as non-obese or lean NAFLD.15 high-income countries, the rise in body-mass index
These patients usually have central obesity or other among children and adolescents has accelerated in east
metabolic risk factors.16 and south Asia.26 Among children, the pooled mean
Although less than 10%17,18 of patients with NAFLD prevalence of NAFLD is 7 6% in the general population
develop cirrhotic complications and hepatocellular and 34 2% in clinics for pediatric obesity.27 Individuals
carcinoma during the 10–20 years after diagnosis, the with disease onset in childhood have a higher risk of
absolute numbers are substantial given the high developing liver-related events and other comorbidities
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NAFLD spectrum
NAFL.36 The histological scoring system for staging
fibrosis ranges from stage 0 (no fibrosis) to stage 4
nafl NASH compensated decompensated (cirrhosis). The natural course of NAFLD is inconstant
cirrhosis cirrhosis
and is characterized by bidirectional and concordant
*
changes in both disease activity and fibrosis stage.39
Fibrosis Nevertheless, the presence of fibrosis, in particular
progression advanced fibrosis (stage 3 and 4), is a key prognostic
marker for liver-related outcomes and overall
mortality.17,18,40 In a meta-analysis of 13 studies
comprising 4428 patients with NAFLD , patients with
hepatocellular
carcinoma stage 4 fibrosis (cirrhosis) had higher all-cause mortality
(relative risk [RR] 3 42, 95% CI 2 63–4 46) and liver-
Factors associated with NAFLD and NASH progression
related mortality (RR 11 13, 4 15 –29 84) than those without fibrosis
Comorbid illness Genetic factors • environmental factors
Although there is substantial collinearity between the
• Type 2 diabetes PNPLA3 • fructose
• Insulin resistance • TM6SF2 • Cholesterol presence of NASH and clinically significant fibrosis, this
• Dyslipidaemia • GCKR • Alcohol collinearity minimizes at the cirrhotic stage as features
• obesity • MBOAT7 • exercise
• HSD17B13 • Coffee
such as steatosis or those specific to NASH might no
• Hypertension
• Hypopituitarism longer be visible.41 Hence, most people with cryptogenic
cirrhosis (cirrhosis of unknow no cause) with metabolic
comorbidities and no other known cause of liver disease
Figure 2: Spectrum of NAFLD
Factors in black have an established association with NAFLD and are likely to have burned-out NASH.42 It is not uncommon
NASH progression (broadly classified into comorbid illness, genetic for individuals with NAFLD to be undiagnosed for
factors, and environmental factors).34 Green indicates a protective factor.
decades, even well after cirrhosis has developed. NAFLD
NAFL=non-alcoholic fatty liver. NAFLD=non-alcoholic fatty liver disease.
NASH=nonalcoholic steatohepatitis. *Fibrosis regression. is often not recognized until patients have evidence of
portal hypertension (eg, splenomegaly, and
associated with metabolic syndrome during their lifetime thrombocytopenia) or develop liver related complications.
than those with disease onset in adulthood.28 Progression from compensated cirrhosis to decompensated
disease (eg, ascites, hepatic encephalopathy, or bleeding
natural history gastro oesophageal varices) with complications of portal
The relationship between NAFLD and all-cause mortality hypertension or liver failure occurs at a rate of
is unresolved, with some studies detecting a modest approximately 3–4% per year.43 Cirrhosis is also the
increase in risk of all-cause mortality compared with the strongest risk factor for the development of hepatocellular
general population,29–31 and others reporting no carcinoma; The Annual Incondume of hepatocellular
association between NAFLD and mortality.32,33 NAFLD carcinoma is 10 · 6 per 1000 person-years in patients
is a heterogeneous condition with varying rates of disease with nash cirrhosis Of cirrhosis is very low (annual
progression and clinical outcomes, which might be driven incidence of 0 08 per 1000 person-years).44 Driven by its
by the varying predominant mechanisms for the high prevalence in the general population, NAFLD is now
development of the disease (figure 2).35 In the majority the second leading cause of end-stage liver disease45
of patients, liver disease is stable or slowly progressive and the second most common cause of primary liver
and will not result in cirrhosis or liver-related death. cancer among adults waiting for liver transplantation in
However, a small proportion of affected individuals the USA.5
develop advanced fibrosis and are at risk of developing
complications of end-stage liver disease and hepatocellular
carcinoma. Recognizing the diversity in disease Similarly in Europe, NAFLD now accounts for 8 4% of
progression and the factors that influence it is instrumental annual transplantations, and among all people receiving
to developing guidance for patient care. a liver transplant, hepatocellular carcinoma was found in
Studies assessing paired liver biopsy samples although a greater proportion of individuals with NAFLD (39 1%)
prone to accuracy and selection bias,36 contribute than without NAFLD (28 9 %, p<0 001).46 Although the
important data on the rate of disease progression. increase in liver transplantation for NASH cirrhosis might
Although fibrosis can develop in livers affected by NAFL partly reflect a higher awareness of NAFLD as a cause of
or NASH, fibrosis progression occurs at a more rapid rate end-stage liver disease, natural history and modeling
in people with NASH, which is likely driven by studies suggest that not only the total, but also the relative
necroinflammation.37,38 A meta-analysis of NAFLD proportion of those with advanced liver disease and liver
studies assessing paired liver biopsy samples found that related outcomes (including hepatocellular carcinoma)
fibrosis worsened by one stage (from baseline stage 0 due to NAFLD, are increasing.20,47
fibrosis) on average during 7 1 years for patients with Despite the risk of progressive liver disease, the leading
NASH and by one stage over 14 3 years for patients with cause of death in patients with NAFLD is cardiovascular

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disease, followed by extrahepatic malignancy (eg,

colorectal cancer or breast cancer). These causes of death
are likely to be due to cardiometabolic risk factors that are
shared in NAFLD and cardiovascular disease, although it ÿ Adipose tissue
ectopic fat
is unclear to what extent NAFLD has a direct causative
Altered organ crosstalk
role in the development of cardiovascular disease.48 The Environmental
ÿ Fatty acids
bidirectional relationship between NAFLD and some risk factors
metabolic syndrome features (particularly type 2 diabetes insulin resistance

genetics
and hypertension), in addition to its characteristic metabolic dysregulation
predisposition Innate immune activation ÿDe-novo lipogenesis
proatherogenic lipid profile,49 is one mechanism by which
NAFLD might increase cardiovascular risk. Patients with Altered gut microbiome
NAFLD have a 1 9-times higher risk of incident cancers ÿLipopolysaccharides ÿLipotoxic lipids
Altered gut permeability concentration
than the general population, particularly cancers involving
the liver, gastrointestinal tract, and uterus.50 The biological
inflammation cellular stress
mechanisms might be driven by the association of NAFLD Tissue regeneration
with visceral adiposity and chronic low -grade inflammation, fibrogenesis
but this mechanism has not yet been determined.51
Patients with NAFLD, particularly those with clinically
significant fibrosis, have a higher risk of severe COVID-19
Figure 3: Multiple pathways and interactions between different organs, affect the pathogenesis
than patients without NAFLD.52 The risk of severe illness of non-alcoholic fatty liver disease
from SARS-CoV-2 infection might be independent of In the setting of environmental risk factors and heritable factors, crosstalk between the liver, adipose tissue,
metabolic comorbidities,52 although diabetes and obesity and gastrointestinal tract leads to systemic inflammation and insulin resistance, resulting in increased hepatic
are also established risk factors. delivery of fatty acids and de-novo lipogenesis. This metabolic milieu leads to the formation of lipotoxic
lipids that contribute to cellular stress with subsequent stimulation of inflammation, tissue regeneration, and fibrogenesis.
pathogenesis
The primary driver of NAFLD is overnutrition, which causes genetic risk variants show a synergistic interaction with
expansion of adipose depots as well as accumulation of obesity.58,59
ectopic fat (figure 3). In this setting, macrophage infiltration Interdependence and crosstalk between the liver and
of the visceral adipose tissue compartment creates a other organs (particularly, adipose tissue and the gut)
proinflammatory state that promotes insulin resistance. might also contribute to metabolic dysregulation and
Inappropriate lipolysis in the setting of insulin resistance inflammation in NAFLD.60–62 Alterations in gut microbiota
results in unabated delivery of fatty acids to the liver, composition are seen in patients with NAFLD and some
which, along with increased de-novo lipogenesis, data suggest that there is a faecal-microbiome signature
overwhelms its metabolic capacity. The imbalance in lipid associated with advanced fibrosis.63,64 However,
metabolism leads to the formation of lipotoxic lipids that confirmation of these bacterial signatures in different
contribute to cellular stress (ie, oxidative stress and patient cohorts and geographic regions controlling for
endoplasmic reticulum stress), inflammasome activation environmental factors is required to determine the
and apoptotic cell death, and subsequent stimulation of signature's clinical significance and use for future
inflammation, tissue regeneration, and fibrogenesis.53,54 diagnostic purposes. Factors produced by bacteria (eg,
Inflammatory and profibrogenic macrophages are lipopolysaccharide or short-chain fatty acids) or derived
implicated in the progression of liver fibrosis and might from bile acid metabolism could influence liver inflammation
also have a role in chronic inflammatory processes in other and disease progression in NAFLD, although as yet, clear
tissues.55 causal effects have not been established.
These pathogenic pathways of NAFLD are influenced
by multiple metabolic, genetic, and microbiome-related Risk stratification and assessment of disease
factors that are not completely understood. NAFLD has a severity
heritable component, with genetic differences between NAFLD is most often diagnosed by imaging, although it
individuals influencing disease risk estimates by 20– can be inferred from clinical risk scores (eg, fatty liver
70%.56 A single-nucleotide polymorphism in the PNPLA3 index) or identified histologically. In routine practice, the
gene is the best characterized genetic variant associated most commonly used test is abdominal ultrasonography
with susceptibility to NAFLD.57 However, known genetic (figure 1D). On abdominal ultrasonography, hepatic
variants account for a small proportion (10–20%) of overall steatosis is characterized by a bright liver echotexture and
heritability,56 although this proportion varies across blurring of the hepatic vasculature.65 Abdominal
populations. These genes or genetic variants might ultrasonography has two important limitations: advanced
influence multiple traits—sometimes with divergent effects fibrosis can coarsen hepatic echotexture and blur vascular
on NAFLD and comorbid conditions such as coronary pattern; and its sensitivity is low when steatosis is mild
artery disease—and several (<30%). MRI-based measurements of hepatic

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liver diseases. However, liver enzyme concentrations can be

Panel: Non-invasive fibrosis scores*
normal in more than half of patients with NAFLD, and correlate
Non-alcoholic fatty liver disease fibrosis score
poorly with the histological severity.73
–1 675 + 0 037 × age (years) + 0 094 × body mass index (kg/m²) + 1 13 × impaired
Traditionally, liver biopsy was used to characterize and quantify
fasting glycaemia or diabetes (yes=1, no=0) + 0 99 × aspartate aminotransferase to
histological features of steatosis, inflammation, hepatocyte
alanine aminotransferase ratio – 0 013 × platelet count (×10ÿ/L)– 0 66 × albumin
ballooning, and fibrosis. However, this invasive procedure is
not suitable for widespread use to assess disease stage or
concentration (g/dL)
• Patients at low risk of advanced fibrosis have a score of less than –1 455 (age
determine progression or response to therapy. In addition to its
<65 years) or less than 0 12 (age ÿ65 years); a score greater than 0 675 is suggestive of
risk and cost, liver biopsy is prone to sampling bias.74
advanced fibrosis Intraobserver and interobserver variability in histological
• Interpret with caution in patients who are younger than 35 years; the score is less
assessment is also well documented in liver biopsy.75,76
accurate in patients who are younger than 35 years
Therefore, researchers have developed and validated several
non-invasive tests for NAFLD.
• There is a high rate of intermediate scores
Fibrosis-4 index for liver fibrosis Among the histological features of NAFLD, the severity of
Age (years) × aspartate aminotransferase concentration (IU/L) liver fibrosis has the strongest correlation with liver-related
morbidity and mortality.40,47 Simple fibrosis scores, such as
platelet count (×109 /L) × ÿ(alanine aminotransferase concentration [IU/L]) the NAFLD fibrosis score, Fibrosis-4 (FIB-4) index, and
aspartate aminotransferase-to-platelet ratio index comprises
• Patients at low risk of advanced fibrosis have an index of less than 1·3 (age <65 years) or demographic, clinical, and routine laboratory parameters and
less than 2·0 (age ÿ65 years); a score greater than 3·25 is suggestive of advanced are inexpensive to use (panel).66 Aspartate aminotransferase
fibrosis is an important component in these scores and tends to
• Interpret with caution in patients who are younger than 35 years; the score is less increase in concentration (relative to alanine aminotransferase)
accurate in patients who are younger than 35 years in advanced fibrosis . Although the overall accuracy of these
*Low platelet count suggestive of advanced fibrosis; concentration of alanine aminotransferase falls and aspartate scores is moderate, they have high negative predictive values
aminotransferase is stable or rises with increasing fibrosis. to exclude advanced liver fibrosis, especially in community and
primary care settings.77 Patients with low fibrosis scores are
also at a low risk of developing liver-related complications.78
For more on non-alcoholic steatosis (eg, MRI proton density fat fraction) can detect as
fatty liver disease fibrosis score see
little as 5% fat and are sensitive to dynamic change, but are
https://www.mdcalc.com/nafld
more often used in the research setting and in clinical trials to Among blood biomarkers, the Enhanced Liver Fibrosis (ELF)
non-alcoholic-fatty-liver
disease-fibrosis-score evaluate the efficacy of NASH treatments, rather than in routine score (combining hyaluronic acid, tissue inhibitor of
For more on the fibrosis-4 practice.66,67 metalloproteinase 1, and amino-terminal propeptide of type III
index for liver fibrosis see https:// procollagen [PIIINP]) has been tested in various cross-sectional
www.mdcalc.com/fibrosis-4-fib Risk factors for progressive disease studies and clinical trials. 79,80 The UK National Institute for
4-index-liver-fibrosis
Type 2 diabetes is associated with a more than two-times Health and Care Excellence suggests that the ELF score be
increased risk of advanced fibrosis, cirrhosis-related used for patients with NAFLD and suggests referring patients
complications, and liver disease mortality (figure 2).68 with a score of 10 51 or higher to hepatologists for evaluation.81
Obesity (ie, body-mass index >30 kg/m²), lipid abnormalities Although available in many parts of the world , ELF is not yet
(ie, low concentrations of HDL cholesterol and high approved by the US Food and Drug Administration (FDA).
concentrations of triglycerides), and hypertension are also Furthermore, performance characteristics of ELF in NAFLD are
associated with an increased risk of severe liver disease, incompletely delineated as they were mostly determined from
although the effect sizes are smaller than for type 2 diabetes.68 cohorts with a high prevalence of advanced fibrosis.82 Pro-C3
Patients with NAFLD who are older than 60 years have a higher is another biomarker that is used to measure the propeptide
prevalence of advanced fibrosis than younger patients,69 cleaved from the intact collagen molecule and indicates
reflecting a longer duration of metabolic dysfunction and liver fibrogenesis. Pro-C3 has been used in early phase clinical trials
disease. A variant of the PNPLA3 gene is associated with to infer the potential effect of new drugs on the prevention of
NAFLD histological severity and development of hepatocellular fibrosis progression.83
carcinoma as well as liver-related and all-cause mortality.56,70,71
However, the clinical role of genotyping of variants has not
been established.72 Another method to estimate liver fibrosis in patients with
NAFLD is to measure liver stiffness by ultrasound based
elastography (eg, vibration-controlled transient elastography,
Non-invasive tests of disease severity point-shear wave elastography, and two-dimensional shear
Clinicians usually use liver enzyme concentrations (eg, serum wave elastography) and magnetic resonance elastography
alanine aminotransferase and aspartate aminotransferase) to (figures 1E, F ).66,84,85 Among these methods, transient
assess and monitor patients with elastography has been most

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extensively evaluated, is widely available, and can be paucity of available effective therapeutic interventions.99
used as a point-of-care test.86 It is also possible to There are also concerns about the possible consequences
estimate hepatic steatosis by controlled attenuation of overdiagnosis of NAFLD, particularly regarding the
parameter measurement at the same time. A liver potential physical harms of research and treatment, and
stiffness cutoff of 6 5–7 9 kPa has approximately 90% psychosocial harms of labeling people with the
sensitivity in excluding stage 3 and 4 fibrosis, whereas disease.100 Additional studies are needed to evaluate
patients with cirrhosis typically have liver stiffness more whether screening would improve clinical outcomes and
than 12–15 kPa.66,84,85,87 The liver Stiffness measure whether it is cost-effective. Nevertheless, once NAFLD
ment also correlates with future risk of hepatocellular is diagnosed, we recommend risk stratification by
carcinoma and cirrhotic complications.88,89 The Baveno assessing for the presence of advanced fibrosis or
VI criteria combine liver stiffness measurement (ÿ20 kPa) cirrhosis, and the evaluation of cardiovascular risk and
by transient elastography with platelet count (<150 × 10ÿ comorbid illnesses.
platelets per L) to identify patients at risk of having Some local health districts and specialty networks are
varicose veins that need treatment, and have been investigating integrated management plans and referral
validated in patients with NAFLD.90,91 pathways for patients with NAFLD.101–105 All pathways
Because many clinical trials are of patients with NASH recommend testing for advanced fibrosis (bridging
(NAFLD activity score of ÿ4 with at least one point each fibrosis [stage 3] and cirrhosis [stage 4]) in patients with
in steatosis, lobular inflammation, and hepatocyte a diagnosis of NAFLD, although the specific testing
ballooning) and fibrosis stage 2 or higher, several groups algorithms vary. Overall, expert opinion favors a
have proposed composite scores to identify these pragmatic, staged approach with inexpensive simple
patients. One example of these composite scores is the fibrosis scores (eg, NAFLD fibrosis score or FIB-4) as a
FibroScan-aspartate aminotransferase (FAST) score, first step to identify individuals at low risk of advanced
which comprises aspartate aminotransferase fibrosis, who can be managed in primary care. Individuals
concentration, liver stiffness, and controlled attenuation with indeterminate or high-risk simple scores require
parameter measurements by FibroScan.92 In different additional assessment with locally available second-line
settings, the FAST score has a C-statistic of 0 ·74–0·95 fibrosis tests (eg, ultrasound-based elastography or
in identifying fibrotic NASH. Similarly, the NIS4 algorithm serum ELF test), and might require referral to secondary
comprises four biomarkers (miR-34a-5p, alpha-2 care for investigation of liver disease or management of
macroglobulin, CHI3L1, and glycated haemoglobin) and advanced fibrosis . Patients without advanced fibrosis at
has a C-statistic of 0·76–0·83.93 Depending on regulatory initial assessment require ongoing monitoring in primary
approval, these scores might be used to select patients care to identify progressive liver disease, and retesting
for pharmacological treatment. 3–5 years after initial assessment has been proposed
(figure 4).106
Prevention, evaluation, and management of NAFLD People with type 2 diabetes have a high prevalence of
in primary care and diabetes NAFLD (40–70%), and are more likely to develop
clinics Since primary care is the initial point of contact advanced fibrosis, cirrhosis, and hepatocellular
for most people with health concerns (including metabolic carcinoma than people without diabetes.107 In addition,
risk factors), primary care clinicians have a key role in multimorbidity and polypharmacy are common in patients
the prevention, diagnosis, risk stratification, and with type 2 diabetes and NAFLD, highlighting a need for
management of NAFLD. Few studies have examined multidisciplinary management to address their complex
primary prevention of NAFLD; nevertheless data suggest health-care needs.108 In secondary care diabetes clinics,
the prevalence
that improved diet quality94 and sustained or increased physical of advanced fibrosis among patients with
activity95–97
reduces the risk of developing NAFLD, even among NAFLD is 10–20%, 109–112 which is two to four times
individuals with high genetic risk.94 Primary-care higher than in primary care. There is increasing
clinicians have a pivotal role in promoting and coordinating recognition that an assessment of NAFLD and liver
lifestyle interventions with dietary modification and fibrosis needs to be incorporated into the routine care of
exercise, and in management of metabolic comorbidities. patients with type 2 diabetes.109 As a result, the
As we now have various non-invasive tests to diagnose American Diabetes Association now recommends that
fatty liver and liver fibrosis, one relevant concern is “Patients with type 2 diabetes and elevated liver enzymes
whether screening for NAFLD is worthwhile, particularly ( alanine aminotransferase) or fatty liver on ultrasound
when patients participate in secondary prevention should be evaluated for the presence of non-alcoholic
programs for diabetes or metabolic syndrome. steatohepatitis and liver fibrosis.”113
Recommendations from hepatology associations However, alanine aminotransferase measurements are
regarding screening patients for NAFLD are inconsistent; notoriously inaccurate and are within the normal range
some guidelines10,98 advocate screening in high-risk in most people with type 2 diabetes and NAFLD; Thus
populations (eg, people with obesity, type 2 diabetes, or with this strategy, many patients with clinically significant
metabolic syndrome) whereas others do not, partly reflectingliver
the disease will not be diagnosed.

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commitment in addition to clear recommendations and

Patients with suspected fatty liver
support from the treatment team. Barriers to weight loss
(eg, financial constraints, medical comorbidities,
Imaging or hepatic steatosis scores Incidental finding during investigations for other education, and little access to healthy food) should be
conditions considered when developing a treatment plan. Although
not considered first-line therapy due to the surgical risk,
bariatric surgery in patients with severe obesity can
lead to substantial (15–25%) durable weight reduction
Fatty liver detected; exclude excess alcohol consumption, viral hepatitis, secondary causes of fatty liver (eg,
use of systemic steroids, tamoxifen and methotrexate), and other liver diseases as appropriate and improvement in liver histological features of NASH
and fibrosis.115 Weight loss improves NAFLD and all
of its associated cardiometabolic comorbidities, which
Diagnosis of non-alcoholic fatty liver disease established
then favorably affects cardiovascular and malignancy
related risk. There is an independent contribution of
Perform simple fibrosis score (eg, FIB-4 and NFS) NASH to cardiovascular and cancer risk but we do not
yet know if liver targeted treatment interventions will reduce them.
Optimizing management with existing

FIB-4 <1 3 (age <65 years) and FIB-4 1·3–3·25 (age <65 years) 4-FIB >3 25; NFS >0 675
<2 0 (age ÿ65 years); NFS less and 2·0–3·25 (age ÿ65 years);
therapeutics There is currently no FDA or European
than –1 455 (age <65 years) NFS –1 455 to 0 675 (age Medicines Agency (EMA) approved therapy for NASH.
and <0 12 (age ÿ65 years) <65 years) and 0 12–0 675 (age
However, several drugs that are currently available for
ÿ65 years)
other indications have been studied in phase 2b trials
for NAFLD (table). Ursodeoxycholic acid, omega-3 fatty
Advanced fibrosis unlikely; Indeterminate results Possible advanced fibrosis acids, and metformin have not shown histological
manage metabolic factors and
benefit, whereas other therapies, such as vitamin E and
retest in 3 years
pioglitazone, have53 and are endorsed by current
guidelines as possible treatment in selected patients
with NASH.99 The benefits of vitamin E (RRR-ÿ-
Use specific fibrosis biomarkers (eg, ELF and elastography) tocopherol [also known as d-ÿ-tocopherol]) for NASH
or refer for specialist care
have been shown in several randomized controlled
trials, including a phase 2b trial in which 84 participants
Figure 4: Proposed diagnostic and referral pathway for non-alcoholic fatty liver disease in primary care were given vitamin E to reduce steatosis and improve
To establish the diagnosis of non-alcoholic fatty liver disease, it is necessary to exclude concomitant liver diseases
and secondary causes of hepatic steatosis. This process usually includes careful documentation of alcohol
histological NASH in patients without diabetes or
consumption and medication intake (eg, systemic steroids, tamoxifen, and methotrexate), and excluding viral cirrhosis.116 In a randomized controlled trial of patients
hepatitis by checking HBsAg and anti-hepatitis C virus antibody. Additional assessment for less common causes of with type 2 diabetes and NASH assigned to 18 months
liver disease would depend on the clinical picture and local epidemiology. ELF=Enhanced Liver Fibrosis score.
of vitamin E alone (n=36), combination therapy of
FIB-4=Fibrosis-4 index. NFS=non-alcoholic fatty liver disease fibrosis score.
vitamin E with pioglitazone (n=37), or a placebo ( n=32),
only those assigned to combination therapy achieved
Management of NASH the histological endpoint (ie, an improvement of NASH
Although the liver related burden of NASH is substantial by >2 points without worsening of fibrosis).120 Vitamin
and increasing, cardiovascular disease and malignancy E use should be considered in the context of its potential
are the leading causes of death in people with adverse effects, which include an increased risk of
NAFLD.4,17,18,20 Therefore, management of NASH bleeding, and its association between higher doses
deserves a holistic approach that strives to minimize and adverse cardio vascular outcomes.99 Although
cardiovascular risk and to reduce drivers of steatosis statins have no discernible histological benefit on NASH
and systemic inflammation. itself, they are safe and should be used as appropriate
The balance between nutrients and energy is pivotal for cardiovascular risk reduction.
in the development of NAFLD and NASH. Central Most individuals with NASH are insulin resistant;121
obesity is an important driver of disease through the however, ameliorating insulin resistance (although
promotion of insulin resistance and proinflammatory signaling. important) is an insufficient therapeutic strategy if used
Although the macronutrient content of the diet is alone. For example, metformin (a weak insulin sensitiser
important, weight loss of more than 5–7% reduces compared with thiazolidinediones) reduces the
hepatic fat content and steatohepatitis, and, for weight progression to type 2 diabetes and is an important
loss in excess of 10%, even fibrosis is reduced in a diabetic treatment, but it has no effect on NASH disease
large proportion of people, irrespective of method of weightactivity. loss.114Conversely, some drugs that improve NASH
Sustained weight loss is challenging because it requires histology have no effect on insulin resistance (eg,
a transformation of ingrained behavior patterns. Even vitamin E, obeticholic acid, and many other drugs in
in the short term, success requires substantial personnel development).116,122,123

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Effects on the liver Quality of evidence Other benefits Key adverse events Contraindications and
cautions
Pioglitazone Improves hepatic Several small* to Improves insulin Weight gain, fluid Contraindicated in patients
steatosis and moderate† phase 2 sensitivity and diabetic retention, bone loss, and with NYHA class III or IV
necroinflammation, and randomized controlled control might increase bladder heart failure; maximum
can improve fibrosis trials116 cancer dose 15 mg if used in
combination with
gemfibrozil or other strong
CYP2C8 inhibitors
Vitamin E Improves hepatic steatosis Several small* to Neutral metabolic A meta-analysis suggests Caution in patients with
and necroinflammation; moderate† randomized effects a small increase in overall high cardiovascular risk
might prevent liver controlled trials; data on mortality at high doses; and those at high risk of
decompensation and clinical outcomes based might increase risk of bleeding
mortality in patients with on a retrospective cohort bleeding, prostate cancer,
advanced liver fibrosis study with propensity heart failure, and
score matching116,117 haemorrhagic stroke
GLP-1 agonists‡ Improves hepatic Several small* to Improves diabetic Nausea, vomiting, Discontinue GLP-1 agonists
steatosis and moderate† randomized control, reduces major dyspepsia, diarrhea, and immediately in case of
necroinflammation controlled trials118 adverse cardiovascular constipation acute pancreatitis; might
events and weight cause acute kidney injury
rarely; semaglutide might
increase diabetic
retinopathy complications
SGLT2 inhibitors§ Improves hepatic Several small* Improves diabetic Genitourinary infection, Contraindicated if
steatosis, randomized controlled control; modest weight acute kidney injury, and estimated glomerular
necroinflammation, and trials with non-invasive reduction; might have euglycaemic diabetic filtration rate is less than
liver enzymes tests; two small* renoprotective benefits; ketoacidosis; might 45 mL/min per 1 73 m²
uncontrolled paired liver Canagliflozin and increase the risk of
biopsy studies119 empagliflozin reduce fractures and limb
major adverse amputations
cardiovascular events
NYHA=New York Heart Association. *Small was defined as less than 50 participants in the active group. †Moderate was defined as 50–100 participants in the active group.
‡For example, liraglutide and semaglutide. §For example, canagliflozin, dapagliflozin, and empagliflozin.
Table: Potential use of off-label therapy for non-alcoholic steatohepatitis
Thiazolidinediones, such as pioglitazone, might prevent endpoints (NASH resolution without worsening of fibrosis;
the development of type 2 diabetes.124 Multiple trials in or an improvement in fibrosis of one stage or more
patients with and without diabetes have shown that without worsening of NASH). These agents have the
pioglitazone improves NASH activity125 with a numerical, additional benefit of inducing weight loss.
but not statically significant, improvement in fibrosis in Semaglutide 0 4 mg/day given subcutaneously was more
phase 2b trials, including a US National Institutes of effective than liraglutide and resulted in an 18% weight
Health sponsored trial by the NASH Clinical Research loss during a 52-week period with similar tolerability.130
Network that had 80 participants in the active Semaglutide 2 4 mg a week given sub cutaneously is
group.116,126 Although pioglitazone-associated average currently being explored in several contexts to manage
weight gain (2 4–4 8 kg) is a side-effect, it is less than obesity.131 All of these classes of drugs are being
the average weight gain associated with insulin (3–10 evaluated for the treatment of NASH.
kg). Another factor limiting widespread use of pioglitazone In a phase 2 randomized controlled trial, subcutaneous
in NASH is the risk of bone loss related to the negative semaglutide 0 4 mg daily reached the primary endpoint
effects of PPAR-ÿ activation on bone remodeling. It of NASH resolution with no worsening of fibrosis in 59%
appears unlikely at this time that either vitamin E or of patients, compared with 17% in the placebo group
pioglitazone will be studied in phase 3 studies; however, (p<0 001).132 It is difficult to discern if these effects are
other drugs that modulate PPAR-ÿ and complementary independent of weight loss; however, the results
mechanisms are being developed. represent the highest rate of NASH resolution ever
reported in NASH therapeutic trials.
For individuals with concomitant type 2 diabetes, there
is a growing list of antidiabetic medications that are Emerging therapeutics of
cardioprotective and renoprotective.127–129 Several of NASH Numerous drugs with different mechanisms of
these medications, including several GLP-1 receptor action, targeting lipid metabolism, inflammatory, or fibrotic
agonists and SGLT2 inhibitors, are currently being pathways, are in development as treatment for NASH.53,133
studied in phase 2 and phase 3 trials to assess their To achieve full FDA approval, a therapeutic intervention
efficacy on one of the two FDA-approved histological is required to show a clinically meaningful benefit, defined

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as an improvement in how a patient feels, functions, or Several drugs are in advanced stages of development
survives. Since most patients with NASH have few liver- for NASH; however, there have already been multiple
specific symptoms, full approval of these drugs will failures related to disease heterogeneity, variable placebo
require the drug to reduce the development of liver- response, low efficacy, and, in some cases,
related events or mortality. Given the course of the overinterpretation of phase 2 results.137 Several phase
disease in NASH—it often takes decades to produce liver- 2b trials that showed favorable efficacy with respect to
related events or death, even in the context of advanced fibrosis—
fat reduction and histological endpoints have already
Ongoing trials are mainly focused on surrogate endpoints, been continued in phase 3 trials, which will provide more definitive d
such as histology, that are reasonably likely to translate Several advanced phase trials that focused on NASH
into clinically meaningful benefit. The FDA is considering cirrhosis have not met their endpoints; however, other
two histological endpoints for conditional approval of trials using promising therapies from non-cirrhotic NASH
NASH therapeutic agents. These endpoints are: NASH trials are ongoing.137 Future treatment will require
resolution without worsening of fibrosis; or an improvement combination therapy in most patients, consisting of a so-
in fibrosis of one stage or more without worsening of called backbone therapy and an additional agent, tailored
NASH. In comparison, EMA requires statistically to the individual. Currently, the independent benefit of
significant improvement in both histological endpoints. drugs in development needs to be shown before
Alternatively, if a therapeutic agent is primarily evaluated combination therapy is approved. Several combination
for its antifibrotic effects, it should show an efficacy in trials are now under way. For example, the ATLAS trial
improving fibrosis by two or more stages. Previously, showed a trend towards greater fibrosis improvement
efficacy of NASH therapeutic agents has been moderate with cilofexor (a farnesoid X receptor agonist) and
with statistical significance hedging on a somewhat firsocostat (an acetyl-CoA carboxylase [ACC1] inhibitor)
unpredictable placebo response rate and variability in than either alone (21% vs 12% improvement) in patients
histological interpretation, which is beyond the scope of with NASH and F3–4 fibrosis.140 Patients receiving this
this Seminar.134 combination treatment were also more likely to have a 2-
REGENERATE, a trial that compared two doses of point or better improvement in the NAFLD activity score
obeticholic acid (a potent farnesoid X receptor agonist) than those receiving monotherapy. However, given the
with placebo, was the first phase 3 trial to meet the modest difference, more effective combinations will be
primary endpoint of an improvement in fibrosis of one needed.
stage or more without worsening of NASH, recapitulating
the findings of the FLINT phase 2b trial.122,123 Although Challenges and prospects
statistically significant, the magnitude of response was Although valuable progress has been made during the
modest, which supports the notion that combination past 40 years in learning about the natural history and
therapy will be required to adequately treat the majority underlying biology of NAFLD, there are still many
of patients. Although obeticholic acid failed to achieve challenges. NAFLD is largely under-recognized by health-
the NASH resolution endpoint, it did improve each of the care professionals and the wider community.
individual histological features of NASH (eg, steatosis, Implementation of strategies to identify, and appropriately
inflammation, and hepatocyte ballooning). The manage, at-risk patients with advanced fibrosis will
REGENERATE trial was the first NASH treatment to require action by clinicians in primary care, diabetes
meet its endpoint; however, two side-effects of the drug clinics, and other specialists who treat patients with
reduced enthusiasm for conditional approval. In the trial, metabolic risk factors, although substantial hurdles, such
pruritus occurred in 51% of patients given 25 mg of as cost and access to second-line tests, will need to be
obeticholic acid, in 28% of those given 10 mg of obeticholic addressed. There is an increasing awareness of the need
acid, and 19% of patients given placebo. The extent to for a multipronged public health response to address
which pruritus can be mitigated with other medications or NAFLD risk factors and the underlying obesogenic
dose reduction while retaining some degree of efficacy is environment.7,141
unknown. Increase in LDL concentration is directly There are several barriers to the development of highly
related to the drug's inhibition of the enzyme CYP7A1 effective therapeutic interventions. One of the most
and can be mitigated with the use of statins.135 The important challenges in the field is a continued reliance
cardiovascular effect of an increase in LDL concentration, on liver biopsy for diagnosis. A reliable biomarker that
or its reduction with a statin, when treated with obeticholic can accurately diagnose and stage NAFLD across the
acid, or more broadly during CYP7A1 inhibition, is not entire disease spectrum does not yet exist.66,142,143 A
yet known. The 2020 decision by the FDA to delay diagnostic biomarker, in conjunction with a prognostic
conditional approval of obeticholic acid until more efficacy biomarker (of which some currently hold promise), would
and safety data are available might reflect some of these allow the identification of high-risk individuals on whose
concerns. The FDA has requested the REGENERATE resources should be concentrated. A second challenge
trial continues so that clinical outcome data can be is the substantial heterogeneity of NAFLD and the current
reviewed in the future.136 limited understanding of disease phenotypes.

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The ability to phenotype patients would permit more 10 European Association for the Study of the Liver, European
accurate prognostication, selection of appropriate Association for the Study of Diabetes, European Association for the Study
of Obesity. EASL–EASD–EASO Clinical Practice Guidelines for the
therapy, and prediction of treatment response than is management of non-alcoholic fatty liver disease. J Hepatol
currently possible. Lastly, the refinement of therapeutic 2016; 64: 1388–402.
11 Eslam M, Newsome PN, Sarin SK, et al. A new definition for
strategies into thoughtful combination approaches,
Metabolic dysfunction-associated fatty liver disease: an international expert
tailored to the patient's individual disease drivers, are consensus statement. J Hepatol 2020; 73: 202–09.
needed for increased response rates and a change in 12 Younossi ZM, Rinella ME, Sanyal A, et al. From NAFLD to MAFLD: implications
our attitude to screening. of a premature change in terminology. Hepatology
2020; published online June 16. https://doi.org/10.1002/hep.31420.
Finally, regardless of the progress that has been, or 13 Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver
will be, made in diagnostic tests and drug treatments, disease: from pathophysiology to therapeutics. metabolism
healthy lifestyle and weight reduction remains crucial 2019; 92: 82–97.
14 Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD
for the prevention and treatment of NAFLD, as obesity
and NASH in patients with type 2 diabetes: a systematic review and
is the main driver of this common liver disease and its meta-analysis. J Hepatol 2019; 71: 793–801.
associated metabolic comorbidities. 15 Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence,
and outcomes of non-obese or lean non-alcoholic fatty liver disease: a
Contributors
systematic review and meta-analysis. Lancet Gastroenterol Hepatol
All authors contributed equally to the Seminar, participating in the literature 2020; 5: 739–52.
search, writing, review, and approval of the final version. 16 Wei JL, Leung JC, Loong TC, et al. Prevalence and severity of
Declaration of interests Nonalcoholic fatty liver disease in non-obese patients: a population study
VW-SW served as a consultant or advisory board member for 3V-BIO, using proton-magnetic resonance spectroscopy.
Am J Gastroenterol 2015; 110: 1306–14.
AbbVie, Allergan, Boehringer Ingelheim, US Center for Outcomes
Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi 17 Angle P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no
Other histologic features, is associated with long-term outcomes of patients
Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum
with nonalcoholic fatty liver disease. Gastroenterology 2015; 149: 389–
Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET-NASH, and 97.e10.
Terns; and served as a speaker for AbbVie, Bristol-Myers Squibb,
18 Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor
Echosens, and Gilead Sciences. VW-SW has also received an unrestricted
for disease-specific mortality in NAFLD after up to 33 years of
grant from Gilead Sciences for fatty liver research. MR is a scientific follow-up. Hepatology 2015; 61: 1547–54.
consultant or advisory board member for Centara, Madrigal, Gilead
19 Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver
Sciences, Genfit, Galecto, Amgen, Alnylam, Thetis, Lipocine, Coherus, NGM diseases. Hepatology 2005; 42: 5–13.
Biopharmaceuticals, Enanta, Immuron, Fractyl, ProSciento, Gelesis, Merck,
20 Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease
Metacrine, Viking Therapeutics , Allergan, Cymabay, Boehringer Ingelheim, burden in China, France, Germany, Italy, Japan, Spain, United
Genentech, Sagimet Bio, Terns, Siemens, Novartis, Bristol Myers Squibb, Kingdom, and United States for the period 2016–2030.
and Intercept Pharmaceuticals. MR has received independent J Hepatol 2018; 69: 896–904.
research funding from Novartis, and owns no stocks and does not participate 21 Estes C, Chan HLY, Chien RN, et al. Modeling NAFLD disease
on speakers bureaus. EEP served as a consultant or advisory board member burden in four Asian regions-2019-2030. Aliment Pharmacol Ther
for CSL Behring and has received an unrestricted grant from Siemens 2020; 51: 801–11.
Healthineers. EEP owns no stocks and does not participate on speakers 22 Allen AM, Van Houten HK, Sangaralingham LR, Talwalkar JA, McCoy
bureaus. RG. Healthcare cost and utilization in nonalcoholic fatty liver disease:
real-world data from a large US claims database.
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Non-alcoholic fatty liver disease

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Figure 1: Histological and radiological assessment of non-alcoholic fatty liver disease

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disease, followed by extrahepatic malignancy (eg,

metabolic syndrome features (particularly type 2 diabetes insulin resistance

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liver diseases. However, liver enzyme concentrations can be

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commitment in addition to clear recommendations and

Optimizing management with existing

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Table: Potential use of off-label therapy for non-alcoholic steatohepatitis

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